Jul 20, 2011

Study of Genetic Alzheimer's Disease Gives Clues to Presymptomatic Detection and Progression of the Disease

Measurable brain chemistry changes may appear 10 to 20 years before the first detectable memory and thinking impairments among people with a rare genetic form of Alzheimer's...

Alzheimer's Reading Room

Randall Bateman

"We want to prevent damage and loss of brain cells by intervening early in the disease process – even before outward symptoms are evident, because by then it may be too late," said Randall Bateman, MD, Assistant Professor of Neurology at the Washington University School of Medicine, Associate Director of the Dominantly Inherited Alzheimer Network (DIAN), and leader of DIAN's Clinical Core.

"We propose accelerating efforts to prevent Alzheimer's by treating people at highest risk for dementia caused by Alzheimer's."

This research focuses on a form of Alzheimer's caused by rare genetic mutations that guarantee a person will develop the disease. Because inheriting a single copy of these genes from either parent causes Alzheimer's, this form of the disease is called "dominantly inherited." It's also known as "autosomal dominant" or "familial" Alzheimer's. People with dominantly inherited Alzheimer's develop symptoms at a young age – usually when they are in their 40s and 50s, but sometimes as early as their 30s. This form of Alzheimer's comprises about 1 percent of cases worldwide.

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International Study of Genetic Alzheimer's Disease Gives Clues to Presymptomatic Detection and Progression of the Disease

The genes that guarantee a person will develop Alzheimer's are known as "deterministic" genes. There are also "risk" genes that increase the likelihood a person will develop Alzheimer's, but don't guarantee that it will happen. In the vast majority of people with Alzheimer's, the disease results from complex interactions among genes, life experiences and other factors.

In 2008, the U.S. National Institute on Aging (NIA) at the National Institutes of Health (NIH) funded the establishment of the DIAN study, conducted by an international network of 11 leading research centers to investigate Alzheimer's caused by the rare, dominantly inherited genetic mutations. Directed by John C. Morris, MD, of Washington University School of Medicine, DIAN now has the largest and most extensive worldwide research network investigating dominantly inherited Alzheimer's at research facilities in the U.S., U.K. and Australia.
People from families with known gene mutations that cause Alzheimer's represent an ideal study group to determine the sequence and rate of Alzheimer's brain changes that occur before detectable memory and thinking changes appear. Asymptomatic mutation carriers – all of whom are destined to develop symptomatic Alzheimer's – can be compared with their noncarrier siblings. However, no single research center has sufficient numbers of familial Alzheimer's individuals to conduct a big enough study to generate meaningful results, underscoring the value of DIAN.

"By studying the cause, progression, detection, treatment and prevention of Alzheimer's in those rare individuals who are destined to get the disease because of their genes, we believe we can learn a great deal more about the vast majority of people whose Alzheimer's develops as a result of complex interactions among their genes, life experiences and other factors," said William Thies, PhD, Chief Medical and Scientific Officer at the Alzheimer's Association. "In particular, earlier detection and treatment are crucial if we are to curb the growing epidemic of Alzheimer's disease."

Details of the DIAN Trial and Interim Results

At AAIC 2011, the DIAN researchers presented the clinical, cognitive, MRI, PET, cerebrospinal fluid (CSF), and blood biomarkers from the first cohort of DIAN participants with respect to the expected age of onset and suggestions on how these measures may be utilized in the design of trials. The DIAN registry will eventually total 400 individuals; at AAIC 2011, the scientists reported data from the initial 150 enrollees.
"Based on what we see in our population, brain chemistry changes can be detected up to 20 years before the expected age of onset," said Bateman. "These Alzheimer's-related changes can be specifically targeted for prevention trials in these patients with genetic Alzheimer's."

Asymptomatic DIAN participants have a mean age of 37 years at entry into the study; just over half (51percent) carry the Alzheimer's gene mutation. The average age at which their parent with Alzheimer's started experiencing symptoms is 45.8 years. Of those people in the study who are symptomatic, mean age of symptom onset is 46.1 years.

To date, the researchers have analyzed samples of CSF and blood from approximately 130 DIAN participants for proteins known to be related to Alzheimer's. These proteins include:

amyloid-beta42, the primary component of amyloid plaques in the Alzheimer's brain

Previous research has shown that levels of CSF amyloid-beta42 are decreased in people who have Alzheimer's dementia compared those without Alzheimer's, reflecting the presence of amyloid plaques in the brain. Levels of tau are elevated, reflecting the presence of neurofibrillary tangles and/or brain cell death. The DIAN researchers asked whether these same patterns of biomarker changes are observed in Alzheimer's mutation carriers while they are still cognitively normal, and when such changes can be detected, with the goal of being able to determine (1) who is in the very earliest (preclinical) stages of the disease and (2) where they are along the course of the disease.

They found that, overall, asymptomatic Alzheimer's mutation carriers in DIAN had lower levels of CSF amyloid-beta42 and higher levels of tau compared to family members who did not have the mutation; this is consistent with the presence of Alzheimer's plaques and tangles even in the preclinical phase of the disease – before there are memory and thinking changes.

Importantly, when they looked at the relationship of these changes in protein levels to the person's expected age of dementia onset (defined as the age of dementia onset of their parents), they found that these biomarker changes were detectable at least 10 years before the expected age of dementia onset. They did not observe this pattern in family members who did not have mutations. These findings suggest that CSF amyloid-beta and tau are useful Alzheimer's markers in individuals destined to develop Alzheimer's dementia, and that absolute levels of these markers may indicate how far along in the disease process these individuals are before cognitive symptoms become apparent.

"This suggests that we can measure brain chemistry abnormalities in the Alzheimer's gene carriers that begin at least 10 years, and maybe even 20 years, before the age that their parents saw Alzheimer's symptoms and when they too would be expected to see them," Bateman said. "As a result, we believe that the DIAN results will help to elucidate the chronology of Alzheimer's disease progression prior to its symptomatic stages."

Note: New criteria and guidelines for the diagnosis of Alzheimer's disease were recently published by the National Institute on Aging and the Alzheimer's Association in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. These new criteria and guidelines describe three stages of the disease – including a research agenda for a proposed preclinical stage to be diagnosed solely by biomarkers. The work being carried out by the DIAN team coincides strongly with the research agenda outlined in those documents and supports the viability of preclinical detection of Alzheimer's.

Imaging

Results in the DIAN population from brain amyloid imaging with C-11 PiB PET suggest that the deposition of amyloid begins many years before the development of dementia symptoms. They also reveal distinct differences in the regional distribution of beta-amyloid in the brain in dominantly inherited Alzheimer's compared to the much more common sporadic late onset Alzheimer's.

"We don't know yet why there are these differences," Bateman said. "For now, it is an observation of one of the few consistent differences between autosomal dominant and sporadic Alzheimer's."
Clinical and Cognitive Assessment

"The DIAN study and findings provide the most extensive data on brain structural and pathologic biomarkers, blood and CSF biomarkers, and cognitive and clinical measures in pre-clinical and symptomatic early onset autosomal dominant Alzheimer's disease. This information fills a gap in the cascade of events causing Alzheimer's and represents a unique opportunity for prevention trials in Alzheimer's disease," Bateman said.

Leveraging the study's existing infrastructure, the DIAN Therapeutic Trials Unit (TTU) plans to implement prevention trials. The U.S. Food and Drug Administration and European Medicines Agency – both government agencies that regulate drug trials – have expressed support for prevention trials in this special population. Eleven compounds have been nominated by the pharmaceutical industry for use in these trials; discussions are ongoing.

"Clinical trials in people with genetic Alzheimer's will pioneer the way to prevention trials for all forms of Alzheimer's," Bateman said.

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